US11986471B2ActiveUtilityA1
Compounds and methods of use
Est. expiryJul 18, 2038(~12 yrs left)· nominal 20-yr term from priority
A61K 31/4725A61K 31/496A61K 31/5377A61K 31/5386C07D 401/14C07D 413/14C07D 498/08
64
PatentIndex Score
0
Cited by
61
References
20
Claims
Abstract
Compounds are provided according to Formula (I):and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X1, X2, X3, X4, Y, A, L1, L2, R1, R2, R5, m and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method of treating a methylthioadenosine phosphorylase-deficient (MTAP-deficient) and/or a methylthioadenosine-accumulating (MTA-accumulating) cancer selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer, bladder cancer, pancreatic cancer, mesothelioma, melanoma, non-small cell lung cancer, astrocytoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach cancer, kidney cancer, breast cancer, cancer of the endometrium, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer and sarcoma in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof wherein the compound is of formula (I)
wherein
X 1 , X 2 , X 3 and X 4 are each independently N or CR x ;
Y is N, CH or CR 5 ;
L 1 is a bond or C 1 -C 4 -alkylene substituted with 0-2 instances of R 6 ;
L 2 is a bond, —NH— or —O—;
Ring A is a carbocycle, heterocycle, 5-6 member monocyclic heteroaryl or a monocyclic aryl;
R 1 is a 3-7 membered carbocycle, a 4-7 membered heterocycle or a 5-6 membered heteroaryl substituted with 0-3 instances of R 4 ;
each R 2 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —CH 2 C(═O)R 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 ;
each R 3 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 carbocyclyl, C 3 -C 7 heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R 4 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NRS(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 ;
each R x is independently selected from hydrogen, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NRS(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 wherein each alkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl is optionally substituted;
each R 5 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 , —S(═O) 2 N(R 3 ) 2 , or two R 5 can be taken together with the atoms to which they are attached to form a —C 3 -C 9 carbocyclyl or a —C 3 -C 9 heterocyclyl;
each R 6 is independently selected from halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 haloalkyl, or two R 6 can be taken together with the atoms to which they are attached to form a C 3 -C 7 carbocycle or a C 3 -C 7 heterocycle;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.
2. The method of claim 1 wherein the compound has structure (Ia)
3. The method of claim 2 wherein the compound has structure (IIa)
4. The method of claim 2 wherein the compound has structure (IVa)
5. The method of claim 2 wherein the compound has structure (IVa)
6. The method of claim 2 wherein the compound has structure (Va1′)
7. The method of claim 6 wherein R x is H, N(R 3 ) 2 , NHR 3 , N(CH 3 )R 3 , OR 3 , C 1 -C 6 alkyl, optionally substituted —C 3 -C 9 carbocyclyl or optionally substituted —C 3 -C 9 heterocyclyl.
8. The method of claim 2 wherein the compound has structure (VIa1′)
9. The method of claim 8 wherein R x is H, N(R 3 ) 2 , NHR 3 , N(CH 3 )R 3 , OR 3 , C 1 -C 6 alkyl, optionally substituted —C 3 -C 9 carbocyclyl or optionally substituted —C 3 -C 9 heterocyclyl.
10. The method of claim 2 wherein the compound has structure (VIIa1)
11. A method of treating a methylthioadenosine phosphorylase-deficient (MTAP-deficient) and/or a methylthioadenosine-accumulating (MTA-accumulating) cancer selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer, bladder cancer, pancreatic cancer, mesothelioma, melanoma, non-small cell lung cancer, astrocytoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach cancer, kidney cancer, breast cancer, cancer of the endometrium, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer and sarcoma in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof wherein the compound is of formula (XI)
wherein:
R 1 is a 3-7 membered carbocycle, a 4-7 membered heterocycle or a 5-6 membered heteroaryl substituted with 0-3 instances of R 4 ;
each R 2 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 ;
each R 3 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 carbocyclyl, C 3 -C 7 heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R 4 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 ;
each R 5 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 , —S(═O) 2 N(R 3 ) 2 , or two R 5 can be taken together with the atoms to which they are attached to form a —C 3 -C 9 carbocyclyl or a —C 3 -C 9 heterocyclyl; and
m is 0, 1, 2 or 3.
12. A method of treating a methylthioadenosine phosphorylase-deficient (MTAP-deficient) and/or a methylthioadenosine-accumulating (MTA-accumulating) cancer selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer, bladder cancer, pancreatic cancer, mesothelioma, melanoma, non-small cell lung cancer, astrocytoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach cancer, kidney cancer, breast cancer, cancer of the endometrium, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer and sarcoma in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof wherein the compound is of formula (XII)
wherein
Ring A is a carbocycle, heterocycle, 5-6 member monocyclic heteroaryl or a monocyclic aryl;
R 1 is a 3-7 membered carbocycle, a 4-7 membered heterocycle or a 5-6 membered heteroaryl substituted with 0-3 instances of R 4 ;
each R 2 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 ;
each R 3 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 carbocyclyl, C 3 -C 7 heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R 4 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 and —S(═O) 2 N(R 3 ) 2 ;
each R 5 is independently selected from ═O, halo, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 1 -C 6 haloalkyl, —C 3 -C 9 carbocyclyl, —C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR 3 , —N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —OC(═O)N(R 3 ) 2 , —S(═O)R 3 , —S(═O) 2 R 3 , —SR 3 , —S(═O)(═NR 3 )R 3 , —NR 3 S(═O) 2 R 3 , —S(═O) 2 N(R 3 ) 2 , or two R 5 can be taken together with the atoms to which they are attached to form a —C 3 -C 9 carbocyclyl or a —C 3 -C 9 heterocyclyl; and
m is 0, 1, 2 or 3.
13. The method of claim 2 wherein R 1 is selected from:
14. The method of claim 2 wherein ring A is piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, azetidinyl, tetrahydropyranyl, 1,4-dioxan-2-yl or morpholinyl.
15. The method of claim 2 wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.3]hexyl, spiro[3.3]heptyl.
16. The method of claim 2 wherein n is 1, R 2 is —C(═O)R 3 and R 3 is C 1 -C 6 alkyl or C 3 -C 7 carbocyclyl.
17. The method of claim 1 wherein the compound is selected from:
Nr.
Structure
14
74
76
96
135
140
161
163
179
194
198
201
203
207
219
233
241
242
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
292
293
294
295
296
297
298
299
300
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
329
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
476
477
478
479
480
481
483
484
485
486
487
488
489
490
491
492
494
495
496
497
499
500
501
502
503
504
505*
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
534
535
536
537
538
539
541
542
543
544
545
548
549
550
551
552
553
554
555
556
557
558
559
560
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648**
649**
650
651
652
653
654
18. The method of claim 12 wherein the compound is selected form:
Nr.
Structure
291
301
328
330
392
416
440
475
482
19. A method of claim 11 wherein the compound is selected from:
Nr.
Structure
493
498
530
533
540
546
547
561
577
578
20. The method of claim 1 wherein the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma, pancreatic cancer pancreatic adenocarcinoma, mesothelioma, melanoma, lung squamous cancer, lung adenocarcinoma, astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer or large intestine cancer.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.